High sensitivity and amenability to miniaturization for field-portable applications have helped to make ion mobility spectrometry (IMS) an important technique for the detection of many compounds, including narcotics, explosives, and chemical warfare agents as described, for example, by G. Eiceman and Z. Karpas in their book entitled “Ion Mobility Spectrometry” (CRC, Boca Raton, 1994), the entire contents of which is incorporated herein by reference. In IMS, gas-phase ion mobilities are determined using a drift tube with a constant electric field. Ions are separated in the drift tube on the basis of differences in their drift velocities. At low electric field strength, for example 200 V/cm, the drift velocity of an ion is proportional to the applied electric field strength, and the mobility, K, which is determined from experimentation, is independent of the applied electric field. Additionally, in IMS the ions travel through a bath gas that is at sufficiently high pressure that the ions rapidly reach constant velocity when driven by the force of an electric field that is constant both in time and location. This is to be clearly distinguished from those techniques, most of which are related to mass spectrometry, in which the gas pressure is sufficiently low that, if under the influence of a constant electric field, the ions continue to accelerate.
E. A. Mason and E. W. McDaniel in their book entitled “Transport Properties of Ions in Gases” (Wiley, New York, 1988), the entire contents of which is incorporated herein by reference, teach that at high electric field strength, for instance fields stronger than approximately 5,000 V/cm, the ion drift velocity is no longer directly proportional to the applied electric field, and K is better represented by KH, a non-constant high field mobility term. The dependence of KH on the applied electric field has been the basis for the development of high field asymmetric waveform ion mobility spectrometry (FAIMS). Ions are separated in FAIMS on the basis of a difference in the mobility of an ion at high field strength, KH, relative to the mobility of the ion at low field strength, K. In other words, the ions are separated due to the compound dependent behavior of KH as a function of the applied electric field strength.
In general, a device for separating ions according to the FAIMS principle has an analyzer region that is defined by a space between first and second spaced-apart electrodes. The first electrode is maintained at a selected dc voltage, often at ground potential, while the second electrode has an asymmetric waveform V(t) applied to it. The asymmetric waveform V(t) is composed of a repeating pattern including a high voltage component, VH, lasting for a short period of time tH and a lower voltage component, VL, of opposite polarity, lasting a longer period of time tL. The waveform is synthesized such that the integrated voltage-time product, and thus the field-time product, applied to the second electrode during each complete cycle of the waveform is zero, for instance VH tH+VL tL=0; for example +2000 V for 10 μs followed by −1000 V for 20 μs. The peak voltage during the shorter, high voltage portion of the waveform is called the “dispersion voltage” or DV, which is identically referred to as the applied asymmetric waveform voltage.
Generally, the ions that are to be separated are entrained in a stream of gas flowing through the FAIMS analyzer region, for example between a pair of horizontally oriented, spaced-apart electrodes. Accordingly, the net motion of an ion within the analyzer region is the sum of a horizontal x-axis component due to the stream of gas and a transverse y-axis component due to the applied electric field. During the high voltage portion of the waveform, an ion moves with a y-axis velocity component given by vH=KHEH, where EH is the applied field, and KH is the high field ion mobility under operating electric field, pressure and temperature conditions. The distance traveled by the ion during the high voltage portion of the waveform is given by dH=vHtH=KHEHtH, where tH is the time period of the applied high voltage. During the longer duration, opposite polarity, low voltage portion of the asymmetric waveform, the y-axis velocity component of the ion is vL=KEL, where K is the low field ion mobility under operating pressure and temperature conditions. The distance traveled is dL=vLtL=KELtL. Since the asymmetric waveform ensures that (VH tH)+(VL tL)=0, the field-time products EHtH and ELtL are equal in magnitude. Thus, if KH and K are identical, dH and dL are equal, and the ion is returned to its original position along the y-axis during the negative cycle of the waveform. If at EH the mobility KH>K, the ion experiences a net displacement from its original position relative to the y-axis. For example, if a positive ion travels farther during the positive portion of the waveform, for instance dH>dL, then the ion migrates away from the second electrode and eventually will be neutralized at the first electrode.
In order to reverse the transverse drift of the positive ion in the above example, a constant negative dc voltage is applied to the second electrode. The difference between the dc voltage that is applied to the first electrode and the dc voltage that is applied to the second electrode is called the “compensation voltage” (CV). The CV prevents the ion from migrating toward either the second or the first electrode. If ions derived from two compounds respond differently to the applied high strength electric fields, the ratio of KH to K may be different for each compound. Consequently, the magnitude of the CV that is necessary to prevent the drift of the ion toward either electrode is also different for each compound. Thus, when a mixture including several species of ions, each with a unique KH/K ratio, is being analyzed by FAIMS, only one species of ion is selectively transmitted to a detector for a given combination of CV and DV. In one type of FAIMS experiment, the applied CV is scanned with time, for instance the CV is slowly ramped or optionally the CV is stepped from one voltage to a next voltage, and a resulting intensity of transmitted ions is measured. In this way a CV spectrum showing the total ion current as a function of CV, is obtained.
Numerous ionization sources, including atmospheric pressure ionization sources, have been described for use with FAIMS. Some examples of ionization sources include MALDI, ESI, nanoelectrospray, picoelectrospray, APCI, laser desorption chemical ionization, photoionization, corona discharge, as non-limiting examples. In addition, detection of ions using several types of detectors, including mass spectrometry is known. Other examples of post-FAIMS ion processing tools include FAIMS, IMS, ion funnels, as some non-limiting examples. The above-mentioned ionization sources and detectors optionally are further assembled into various tandem arrangements, including ESI-FAIMS-funnel-IMS-funnel-MS, or ESI-FAIMS-FAIMS trap-IMS-funnel-MS, as two very complex but non-limiting examples of tandem instruments with practical importance in chemical analysis.
In an analytical instrument that includes (1) an atmospheric pressure ionization source, such as for example electrospray ionization (ESI), (2) an atmospheric pressure gas phase ion separator, such as for example high-field asymmetric waveform ion mobility spectrometer (FAIMS) and (3) a detection system, such as for example mass spectrometry, (MS) it is advantageous to provide each with independent control of some of the operating conditions including temperature, operating gas pressure, and operating gas composition. In these regards, the ion source, FAIMS and mass spectrometer have significantly different requirements for optimum performance.
The performance of FAIMS for separation of ions may be dependent on temperature. For example an elevation in temperature may cause peaks in a CV spectrum to widen because of an increase in ion diffusion. Under this condition two ions that are separated at room temperature fail to be separated at 100° C., for example. Similarly, two ions that fail to separate at room temperature are separated at 10° C. with cooled FAIMS electrodes, for example.
Furthermore, the efficiency of transmission of ions through FAIMS is a function of temperature. For example, some types of ions are subject to thermal dissociation and therefore are more efficiently transmitted through FAIMS in a cool bath gas.
Furthermore, the separation of ions is a function of the composition of the carrier gas. Some mixtures of gases, including nitrogen plus helium, and helium plus carbon dioxide, as some non-limiting examples, are known to significantly affect the compensation voltage of the transmission of some ions. These mixtures of gases optionally are controlled and selected to separate ions which otherwise are not separated in any one pure type of carrier gas. Prior U.S. Pat. No. 6,774,360 describes the method and apparatus for improvements in separation and sensitivity in FAIMS, and is included herein by reference. Related patent publications WO 03/067237 and WO 03/067242 describe detection of traces of gases in FAIMS using the shift of CV of a monitor ion, and also are included herein by reference. The CV of the monitor ion shifts because the presence of the trace gas changes the carrier gas composition and therefore changes the optimum conditions for the transmission of the monitor ion.
Furthermore, the separation of ions and the efficiency of ion transmission in the FAIMS analyzer are a function of many mechanical electrode dimensions and a function of many aspects of the voltages and experimental conditions used in FAIMS. For example, the resolution of the separation in FAIMS is a function of the diameters of the electrodes, the width of the analyzer region between the electrodes, the length of time that the ions reside within the analyzer region, the longitudinal location of the inner electrode (domed type electrodes), the frequency of the applied asymmetric waveform, the shape of the asymmetric waveform (square vs two or more superimposed sinusoidal waves), the peak voltage of the asymmetric waveform (DV), as some non-limiting examples. A skilled user of FAIMS adjusts these parameters, and others, to achieve separations.
Accordingly, it would be advantageous to provide control of a number of non-mechanical experimental parameters that impact on the separation of ions, including the temperature of one or both FAIMS electrodes, the pressure of the carrier gas in the FAIMS analyzer, the temperature gradient across the analyzer region of FAIMS, and the composition of the gas mixture used as the carrier gas in the FAIMS analyzer, as some non-limiting examples. These parameters optionally are adjusted independently, or in conjunction with each other, to achieve the performance that is desired.
A method and apparatus for control of the temperature of the ionization source of FAIMS has been described in U.S. Pat. No. 5,736,739 and is incorporated herein by reference. The methods and apparatus for independent control of temperatures and pressures of the ion sources and FAIMS systems was first introduced in previously filed U.S. provisional applications 60/536,707 and 60/572,116 which are incorporated by reference herein. In these filings it was shown to be advantageous to design cylindrical FAIMS and parallel plate FAIMS with independent control of temperatures of the two electrodes to permit adjustment of the two electrodes to be at different temperatures, and at temperatures that differ from the average temperature of the carrier gas. Appropriate selection of these temperatures produces temperature gradients in the gas across the analyzer region, to beneficially influence the ion transmission efficiency and the separation of ions during their passage through the analyzer region.
Certain mixtures of carrier gases are known to significantly impact on the performance of FAIMS. Examples of reports in the scientific literature describing this impact include a paper by Barnett, D. A.; Purves, R. W.; Ells, B. Guevremont, R., entitled “Separation of ortho-, meta-, and para-phthalic acids by high-field asymmetric wavefrom ion mobility spectrometry using mixed carrier gases, ” in J. Mass Spectrom. 2000, 35, 976-980 and a paper authored by Shvartsburg, A.; Tang, K.; Smith, R. D., entitled “Understanding and designing field asymmetric waveform ion mobility separations in gas mixtures, ” in Analytical Chemistry 2004, 76, 7366-7374, the entire contents of both of which are incorporated herein by reference. For example, additions of carbon dioxide (1% to 20% by volume) to a carrier gas of nitrogen increases the CV of transmission and the efficiency of transmission for many low-mass ions, as a non-limiting example.